Genome-wide RNA structure changes during human neurogenesis modulate gene regulatory networks.

The distribution, dynamics, and function of RNA structures in human development are under-explored. Here, we systematically assayed RNA structural dynamics and their relationship with gene expression, translation, and decay during human neurogenesis. We observed that the human ESC transcriptome is globally more structurally accessible than differentiated cells and undergoes extensive RNA structure changes, particularly in the 3' UTR. Additionally, RNA structure changes during differentiation are associated with translation and decay. We observed that RBP and miRNA binding is associated with RNA structural changes during early neuronal differentiation, and splicing is associated during later neuronal differentiation. Furthermore, our analysis suggests that RBPs are major factors in structure remodeling and co-regulate additional RBPs and miRNAs through structure. We demonstrated an example of this by showing that PUM2-induced structure changes on LIN28A enable miR-30 binding. This study deepens our understanding of the widespread and complex role of RNA-based gene regulation during human development.

Leveraging gene co-regulation to identify gene sets enriched for disease heritability.

Identifying gene sets that are associated to disease can provide valuable biological knowledge, but a fundamental challenge of gene set analyses of GWAS data is linking disease-associated SNPs to genes. Transcriptome-wide association studies (TWASs) detect associations between the genetically predicted expression of a gene and disease risk, thus implicating candidate disease genes. However, causal disease genes at TWAS-associated loci generally remain unknown due to gene co-regulation, which leads to correlations across genes in predicted expression. We developed a method, gene co-regulation score (GCSC) regression, to identify gene sets that are enriched for disease heritability explained by predicted expression. GCSC regresses TWAS chi-square statistics on gene co-regulation scores reflecting correlations in predicted gene expression; a gene set is enriched for heritability if genes with high co-regulation to the set have higher TWAS chi-square statistics than genes with low co-regulation to the set, beyond what is expected based on co-regulation to all genes. We verified via simulations that GCSC is well calibrated and well powered. We applied GCSC to gene expression data from GTEx (48 tissues) and GWAS summary statistics for 43 independent diseases and complex traits analyzing a broad set of biological pathways and specifically expressed gene sets. We identified many enriched sets, recapitulating known biology. For Alzheimer disease, we detected evidence of an immune basis, and specifically a role for antigen presentation, in analyses of both biological pathways and specifically expressed gene sets. Our results highlight the advantages of leveraging gene co-regulation within the TWAS framework to identify enriched gene sets.

The CGG repeat expansion in RILPL1 is associated with oculopharyngodistal myopathy type 4.

Recent studies indicate that CGG repeat expansions in LRP12, GIPC1, and NOTCH2NLC are associated with oculopharyngodistal myopathy (OPDM) types 1, 2, and 3, respectively. However, some clinicopathologically confirmed OPDM cases continue to have unknown genetic causes. Here, through a combination of long-read whole-genome sequencing (LRS), repeat-primed polymerase chain reaction (RP-PCR), and fluorescence amplicon length analysis PCR (AL-PCR), we found that a CGG repeat expansion in the 5' UTR of RILPL1 is associated with familial and simplex OPDM type 4 (OPDM4). The number of repeats ranged from 139 to 197. Methylation analysis indicates that the methylation levels in RILPL1 were unaltered in OPDM4 individuals. Analyses of muscle biopsies suggested that the expanded CGG repeat might be translated into a toxic poly-glycine protein that co-localizes with p62 in intranuclear inclusions. Moreover, analyses suggest that the toxic RNA gain-of-function effects also contributed to the pathogenesis of this disease. Intriguingly, all four types of OPDM have been found to be associated with the CGG repeat expansions located in 5' UTRs. This finding suggests that a common pathogenic mechanism, driven by the CGG repeat expansion, might underlie all cases of OPDM.

CoRegNet: unraveling gene co-regulation networks from public RNA-Seq repositories using a beta-binomial statistical model.

Millions of RNA sequencing samples have been deposited into public databases, providing a rich resource for biological research. These datasets encompass tens of thousands of experiments and offer comprehensive insights into human cellular regulation. However, a major challenge is how to integrate these experiments that acquired at different conditions. We propose a new statistical tool based on beta-binomial distributions that can construct robust gene co-regulation network (CoRegNet) across tens of thousands of experiments. Our analysis of over 12 000 experiments involving human tissues and cells shows that CoRegNet significantly outperforms existing gene co-expression-based methods. Although the majority of the genes are linearly co-regulated, we did discover an interesting set of genes that are non-linearly co-regulated; half of the time they change in the same direction and the other half they change in the opposite direction. Additionally, we identified a set of gene pairs that follows the Simpson's paradox. By utilizing public domain data, CoRegNet offers a powerful approach for identifying functionally related gene pairs, thereby revealing new biological insights.

PhosphoDisco: A Toolkit for Co-regulated Phosphorylation Module Discovery in Phosphoproteomic Data.

Kinases are key players in cancer-relevant pathways and are the targets of many successful precision cancer therapies. Phosphoproteomics is a powerful approach to study kinase activity and has been used increasingly for the characterization of tumor samples leading to the identification of novel chemotherapeutic targets and biomarkers. Finding co-regulated phosphorylation sites which represent potential kinase-substrate sets or members of the same signaling pathway allows us to harness these data to identify clinically relevant and targetable alterations in signaling cascades. Unfortunately, studies have found that databases of co-regulated phosphorylation sites are only experimentally supported in a small number of substrate sets. To address the inherent challenge of defining co-regulated phosphorylation modules relevant to a given dataset, we developed PhosphoDisco, a toolkit for determining co-regulated phosphorylation modules. We applied this approach to tandem mass spectrometry based phosphoproteomic data for breast and non-small cell lung cancer and identified canonical as well as putative new phosphorylation site modules. Our analysis identified several interesting modules in each cohort. Among these was a new cell cycle checkpoint module enriched in basal breast cancer samples and a module of PRKC isozymes putatively co-regulated by CDK12 in lung cancer. We demonstrate that modules defined by PhosphoDisco can be used to further personalized cancer treatment strategies by establishing active signaling pathways in a given patient tumor or set of tumors, and in providing new ways to classify tumors based on signaling activity.

Assassination tango: an NLR/NLR-ID immune receptors pair of rapeseed co-operates inside the nucleus to activate cell death.

Plant immunity largely relies on intracellular nucleotide-binding domain leucine-rich repeat (NLR) immune receptors. Some plant NLRs carry integrated domains (IDs) that mimic authentic pathogen effector targets. We report here the identification of a genetically linked NLR-ID/NLR pair: BnRPR1 and BnRPR2 in Brassica napus. The NLR-ID carries two ID fusions and the mode of action of the pair conforms to the proposed "integrated sensor/decoy" model. The two NLRs interact and the heterocomplex localizes in the plant-cell nucleus and nucleolus. However, the BnRPRs pair does not operate through a negative regulation as it was previously reported for other NLR-IDs. Cell death is induced only upon co-expression of the two proteins and is dependent on the helper genes, EDS1 and NRG1. The nuclear localization of both proteins seems to be essential for cell death activation, while the IDs of BnRPR1 are dispensable for this purpose. In summary, we describe a new pair of NLR-IDs with interesting features in relation to its regulation and the cell death activation.

Higher-order modular regulation of the human proteome.

Operons are transcriptional modules that allow bacteria to adapt to environmental changes by coordinately expressing the relevant set of genes. In humans, biological pathways and their regulation are more complex. If and how human cells coordinate the expression of entire biological processes is unclear. Here, we capture 31 higher-order co-regulation modules, which we term progulons, by help of supervised machine-learning on proteomics data. Progulons consist of dozens to hundreds of proteins that together mediate core cellular functions. They are not restricted to physical interactions or co-localisation. Progulon abundance changes are primarily controlled at the level of protein synthesis and degradation. Implemented as a web app at www.proteomehd.net/progulonFinder, our approach enables the targeted search for progulons of specific cellular processes. We use it to identify a DNA replication progulon and reveal multiple new replication factors, validated by extensive phenotyping of siRNA-induced knockdowns. Progulons provide a new entry point into the molecular understanding of biological processes.

Transcription factor expression is the main determinant of variability in gene co-activity.

Many genes are co-expressed and form genomic domains of coordinated gene activity. However, the regulatory determinants of domain co-activity remain unclear. Here, we leverage human individual variation in gene expression to characterize the co-regulatory processes underlying domain co-activity and systematically quantify their effect sizes. We employ transcriptional decomposition to extract from RNA expression data an expression component related to co-activity revealed by genomic positioning. This strategy reveals close to 1,500 co-activity domains, covering most expressed genes, of which the large majority are invariable across individuals. Focusing specifically on domains with high variability in co-activity reveals that contained genes have a higher sharing of eQTLs, a higher variability in enhancer interactions, and an enrichment of binding by variably expressed transcription factors, compared to genes within non-variable domains. Through careful quantification of the relative contributions of regulatory processes underlying co-activity, we find transcription factor expression levels to be the main determinant of gene co-activity. Our results indicate that distal trans effects contribute more than local genetic variation to individual variation in co-activity domains.

From co-regulation to self-regulation: Maternal soothing strategies and self-efficacy in relation to maternal reports of infant regulation at 3 and 7 months.

This study, conducted in Germany, examines the role of maternal soothing strategies to explain the association of maternal self-efficacy with infant regulation (crying and sleeping behavior). Questionnaire data of 150 mothers, living in Germany, with mixed ethnic and educational backgrounds were collected when infants were 3 and 7 months old. Two types of maternal soothing strategies were distinguished: close soothing, involving close physical and emotional contact, and distant soothing, involving physical and emotional distancing from the infant. A cross-sectional SEM at 3 months indicated that maternal self-efficacy is associated with reported infant regulation through distant soothing strategies. Low maternal self-efficacy was associated with frequent maternal use of distant soothing, which in turn was related to reported infant regulation problems, that is, non-soothability and greater crying frequency. Frequent use of close soothing was associated with reported infant sleeping behavior, that is, frequent night-time awakenings. A longitudinal SEM further indicated that the effects of close soothing persisted at least until the infants' age of 7 months. The study showed how low maternal self-efficacy, increased use of distant soothing, and reported early infant regulation problems are intertwined and that, due to their persisting positive effect on infant soothability, close soothing better supports infant development.

Este estudio examina el papel de las estrategias calmantes maternas para explicar la asociación entre auto efectividad materna y la regulación del infante (comportamiento de llanto y de dormir). Información de cuestionario de N = 150 madres de trasfondos étnicos y educativos mixtos se recogió cuando los infantes tenían tres y siete meses de nacidos. Dos tipos de estrategias calmantes maternas se identificaron: estrategia calmante cercana, la cual trata del contacto físico y emocional cercano, y estrategia calmante distante, la cual trata del distanciamiento físico y emocional con el infante. Un estudio de Modelo de Ecuación Estructural (SEM) transversal a los tres meses indicó que la auto efectividad materna se asocia con la reportada regulación del infante a través de estrategias calmantes distantes. La baja auto efectividad materna se asoció con el frecuente uso materno de estrategias calmantes distantes, lo cual a su vez se relacionó con los reportados problemas de regulación del infante, tales como el no calmarse y la mayor frecuencia del llanto. El uso frecuente de estrategias calmante cercanas se asoció con el reportado comportamiento de dormir del infante, tal como el frecuente despertar nocturno. Un estudio de tipo SEM longitudinal indicó más allá que los efectos de las estrategias calmantes cercanas persistían por lo menos hasta que los infantes tenían siete meses de edad. El estudio mostró cómo la baja auto efectividad materna, el uso incrementado de estrategias calmantes distantes, así como los reportados tempranos problemas de regulación del infante están entremezclados y que, debido a su persistente efecto positivo en calmar al infante, las estrategias calmantes cercanas apoyan mejor el desarrollo del infante.

Cette étude examine le rôle des stratégies maternelles d'apaisement pour expliquer le lien de l'auto-efficacité maternelle avec la régulation du nourrisson (pleurs et comportement du sommeil). Des données d'une questionnaire de N = 150 mères issues de milieux ethniques et éducationnels différents ont été recueillies quand les nourrissons avaient trois et sept mois. Deux types de stratégies maternelles d'apaisement ont été distingués: l'apaisement proche, avec un contact physique et émotionnel proche, et l'apaisement distant, avec une distanciation physique et émotionnelle du nourrisson. Une coupe transversale SEM à trois mois a indiqué que l'auto-efficacité maternelle est liée à la régulation infantile signalée au travers de stratégies d'apaisement distantes. Une auto-efficacité maternelle faible était liée à l'utilisation maternelle fréquente de stratégies d'apaisement, qui à son tour était liée aux problèmes signalés de régulation du nourrisson, comme par exemple le fait de ne pas pouvoir être apaisé ou une fréquence de pleurs plus grande. L'utilisation fréquente de stratégies d'apaisement proche était liée au comportement de sommeil du nourrisson signalé, comme par exemple des réveils nocturnes fréquents. Un SEM longitudinal a de surcroit indiqué que les effets de stratégies d'apaisement proches persistaient au moins jusqu'à l'âge de sept mois des nourrissons. L'étude a montré comment l'auto-efficacité maternelle faible, une utilisation accrue de stratégies d'apaisement distant et les problèmes signalés de régulation précoce des nourrissons sont imbriqués et que, du fait de leur effet positif persistant sur l'apaisement du nourrisson, les stratégies d'apaisement proches soutiennent mieux le développement du nourrisson.

A comprehensive survey for human transcription factors on expression, regulation, interaction, phenotype and cancer survival.

Transcription factors (TFs) act as key regulators in biological processes through controlling gene expression. Here, we conducted a systematic study for all human TFs on the expression, regulation, interaction, mutation, phenotype and cancer survival. We revealed that the average expression levels of TFs in normal tissues were lower than 50% expression of non-TFs, whereas TF expression was increased in cancers. TFs that are specifically expressed in an individual tissue or cancer may be potential marker genes. For instance, TGIF2LX/Y were preferentially expressed in testis and NEUROG1, PRDM14, SRY, ZNF705A and ZNF716 were specifically highly expressed in germ cell tumors. We found different distributions of target genes and TF co-regulations in different TF families. Some small TF families have huge protein interaction pairs, suggesting their central roles in transcriptional regulation. The bZIP family is a small family involving many signaling pathways. Survival analysis indicated that most TFs significantly affect survival of one or more cancers. Some survival-related TFs were also specifically highly expressed in the corresponding cancer types, which may be potential targets for cancer therapy. Finally, we identified 43 TFs whose mutations were closely correlated to survival, suggesting their cancer-driven roles. The systematic analysis of TFs provides useful clues for further investigation of TF regulatory mechanisms and the role of TFs in diseases.

The co-regulation of the gut microbiome and host genes might play essential roles in metformin gastrointestinal intolerance.

Metformin is commonly used, but approximately 20% of patients experience gastrointestinal intolerance, leading to medication discontinuation for unclear reasons and a lack of effective management strategies. In this study, the 18 fecal and blood samples were analyzed using 16S rRNA and mRNA transcriptome, respectively. These samples included 3 fecal and 4 blood from metformin-tolerant T2D patients before and after metformin treatment (T and Ta), 3 fecal and 5 blood from metformin-intolerant T2D patients before and after treatment (TS and TSa), and 6 fecal samples from healthy controls. The results showed that certain anti-inflammatory gut bacteria and gene, such as Barnesiella (p = 0.046), Parabacteroides goldsteinii (p = 0.016), and the gene JUND (p = 0.0002), exhibited higher levels in metformin-intolerant patients, and which decreased after metformin treatment (p < 0.05). This potentially invalidates patients' anti-inflammatory effect and intestinal mucus barrier protection, which may lead to alterations in intestinal permeability, decreased gut barrier function, and gastrointestinal symptoms, including diarrhea, bloating, and nausea. After metformin treatment, primary bile acids (PBAs) production species: Weissella confusa, Weissella paramesenteroides, Lactobacillus brevis, and Lactobacillus plantarum increased (p < 0.05). The species converting PBAs to secondary bile acids (SBAs): Parabacteroides distasonis decreased (p < 0.05). This might result in accumulation of PBAs, which also may lead to anti-inflammatory gene JUND and SQSTM1 downregulated. In conclusion, this study suggests that metformin intolerance may be attributed to a decrease in anti-inflammatory-related flora and genes, and also alterations in PBAs accumulation-related flora. These findings open up possibilities for future research targeting gut flora and host genes to prevent metformin intolerance.

Evolution of enzyme levels in metabolic pathways: A theoretical approach. Part 2.

Metabolism is essential for cell function and adaptation. Because of their central role in metabolism, kinetic parameters and enzyme concentrations are under constant selective pressure to adapt the fluxes of the metabolic networks to the needs of the organism. In line with various studies dealing with enzyme evolution, we recently developed a model of the evolution of enzyme concentrations under selection for increased flux, considered as a proxy for fitness (Coton et al., 2022). With this model, taking into account two realistic cellular constraints, competition for resources and co-regulation, we determined the evolutionary equilibria and range of neutral variations of enzyme concentrations. In this article, we expanded this model by considering that the enzymes in a pathway can belong to different co-regulation groups. We determined the equilibria and showed that the constraints modify the adaptive landscape by limiting the number of independent dimensions. We also showed that any trade-off between enzyme concentrations is sufficient to limit the flux and relax selection for increasing the concentration of other enzymes. Even though this model is based on simplifying assumptions, the complexity of the relationship between enzyme concentrations prevents the formal analysis of the range of neutral variation of enzyme concentrations. However, we could show that selection for maximizing the flux results in selective neutrality for all enzymes regardless the constraints applied, giving generality to the prediction of Hartl et al. (1985).

Co-Regulation as a Support for Older Youth in the Context of Foster Care: a Scoping Review of the Literature.

Co-regulation is a relatively new theoretical framework for interventions that connects developmental science to adolescent needs and provides strategies that can be applied across contexts. It also has value in shifting the focus of interventions to the role of relationships and interactions with caring adults, as well as supportive environments. This framework may be particularly salient for older youth with foster care experience whose relationships with adults and availability of developmental supports are disrupted. To understand how co-regulation aligns with current understanding of needs and supports for this population, we conducted a scoping review that involved systematically searching four databases, coding and charting relevant information, and actively engaging expert consultants and other stakeholders. Across 46 primarily descriptive articles, co-regulation was discussed most often in relation to relationships, as expected (89% of articles). Despite theoretical and empirical evidence of the benefits of supportive environments and intentional day-to-day interactions in promoting developmental skills and competencies, these two domains of co-regulation were referenced much less (39% and 28%, respectively). Results highlight opportunities for co-regulation supports that can be provided to older youth with foster care experience by caring adults and near-aged peers in a wide range of roles. Notable limitations in the literature were identified in applying co-regulation within the context of employment and career readiness, healthy relationships, and teen parenting. Also under-researched is the role of adult self-regulation skills and co-regulation approaches for youth from diverse backgrounds, including those who identify as LGBTQ or have disabilities. Considerations for practice and future research are provided.

Evolution of enzyme levels in metabolic pathways: A theoretical approach. Part 1.

The central role of metabolism in cell functioning and adaptation has given rise to countless studies on the evolution of enzyme-coding genes and network topology. However, very few studies have addressed the question of how enzyme concentrations change in response to positive selective pressure on the flux, considered a proxy of fitness. In particular, the way cellular constraints, such as resource limitations and co-regulation, affect the adaptive landscape of a pathway under selection has never been analyzed theoretically. To fill this gap, we developed a model of the evolution of enzyme concentrations that combines metabolic control theory and an adaptive dynamics approach, and integrates possible dependencies between enzyme concentrations. We determined the evolutionary equilibria of enzyme concentrations and their range of neutral variation, and showed that they differ with the properties of the enzymes, the constraints applied to the system and the initial enzyme concentrations. Simulations of long-term evolution confirmed all analytical and numerical predictions, even though we relaxed the simplifying assumptions used in the analytical treatment.

Parent and child self- and co-regulation during pediatric venipuncture: Exploring heart rate variability and the effects of a mindfulness intervention.

Needle procedures are common throughout childhood and often elicit distress in children and parents. Heart rate variability (HRV), as an index of emotion regulation, can inform both self-regulatory and co-regulatory processes. Mindfulness may serve to regulate distress; however, no research has studied mindfulness or parent and child regulatory responding concurrently during venipuncture. Stemming from a randomized controlled trial investigating a mindfulness intervention, this study sought to describe regulatory responding (via HRV) throughout pediatric venipuncture and the role of cognitive-affective factors (mindfulness, parent anxiety, catastrophizing) in 61 parent-child dyads (7-12 years). We examined (1) patterns of parent and child HRV throughout venipuncture and whether a brief, randomly assigned audio-guided mindfulness versus control exercise affected this pattern and (2) the extent to which changes in parent and child HRV were synchronized throughout venipuncture, and whether parent catastrophizing and anxiety moderated this association. HRV differed as a function of procedural phase. Practicing the mindfulness versus control exercise did not consistently affect HRV in dyads. Positive synchrony was observed during the end of the intervention in dyads with high parental catastrophizing. Otherwise, a pattern of nonsynchrony emerged. Results provide foundational knowledge regarding children's internal (self) and external (parent) regulation mechanisms. RCT registration: NCT03941717.

Rethinking Sampled-Data Control for Unmanned Aircraft Systems.

Unmanned aircraft systems are expected to provide both increasingly varied functionalities and outstanding application performances, utilizing the available resources. In this paper, we explore the recent advances and challenges at the intersection of real-time computing and control and show how rethinking sampling strategies can improve performance and resource utilization. We showcase a novel design framework, cyber-physical co-regulation, which can efficiently link together computational and physical characteristics of the system, increasing robust performance and avoiding pitfalls of event-triggered sampling strategies. A comparison experiment of different sampling and control strategies was conducted and analyzed. We demonstrate that co-regulation has resource savings similar to event-triggered sampling, but maintains the robustness of traditional fixed-periodic sampling forming a compelling alternative to traditional vehicle control design.

Prenatal mother-father cortisol linkage predicts infant executive functions at 24 months.

The present study investigated associations between prenatal mother-father cortisol linkage and infant executive functions. Data come from an international sample (N = 358) of predominantly white and middle- to upper-class first-time parents. During late pregnancy, parents collected diurnal salivary cortisol samples and reported on levels of psychological stress. At 24 months, children completed a battery of executive function tasks. Parent cortisol linkage was operationalized as the time-dependent, within-dyad association between maternal and paternal diurnal cortisol. Results indicated that prenatal linkage was positively related to infant executive functions, suggesting that stronger mother-father cortisol linkage was associated with higher executive function scores. Additionally, this relation was moderated by paternal average cortisol levels such that executive function scores were lower when fathers had higher average cortisol levels and linkage was weak. This association suggests that elevated paternal cortisol amplifies the negative relation between lower cortisol linkage and lower infant executive function scores. Importantly, these findings were observed while controlling for observational measures of caregiving and self-report measures of psychosocial functioning and infant social-emotional behavior. These results suggest that prenatal linkage of mother's and father's stress physiology plays a potentially important part in programming and regulating infant neurocognitive development.

The role of co-regulation of stress in the relationship between perceived partner responsiveness and binge eating: A dyadic analysis.

The main aim of this study is to investigate whether there are relationships between perceived partner responsiveness (PPR), co-regulation of negative affect between romantic partners and binge eating. Data were collected from 148 opposite-sex romantic partners (18-61 years old) with the mean relationship duration being 8.04 years. Dyadic data were analysed through the actor-partner interdependence model framework. We proposed a model where co-regulation between partners has indirect effects on the relationship between PPR and binge eating. Results showed that there was no direct association between PPR and binge eating scores of the participants. However, significant direct associations were found regarding both actor and partner effects of PPR on co-regulation between romantic partners. In addition, there were four significant indirect effects: Women's co-regulation had an indirect effect on the link between PPR and women's binge eating scores. Similarly, women's co-regulation had also a significant indirect effect on the link between PPR and men's binge eating. These findings are the first to illustrate a relationship between PPR and binge eating. This study is the first attempt to examine binge eating in terms of co-regulation processes.

DiNeR: a Differential graphical model for analysis of co-regulation Network Rewiring.

BACKGROUND: During transcription, numerous transcription factors (TFs) bind to targets in a highly coordinated manner to control the gene expression. Alterations in groups of TF-binding profiles (i.e. "co-binding changes") can affect the co-regulating associations between TFs (i.e. "rewiring the co-regulator network"). This, in turn, can potentially drive downstream expression changes, phenotypic variation, and even disease. However, quantification of co-regulatory network rewiring has not been comprehensively studied. RESULTS: To address this, we propose DiNeR, a computational method to directly construct a differential TF co-regulation network from paired disease-to-normal ChIP-seq data. Specifically, DiNeR uses a graphical model to capture the gained and lost edges in the co-regulation network. Then, it adopts a stability-based, sparsity-tuning criterion -- by sub-sampling the complete binding profiles to remove spurious edges -- to report only significant co-regulation alterations. Finally, DiNeR highlights hubs in the resultant differential network as key TFs associated with disease. We assembled genome-wide binding profiles of 104 TFs in the K562 and GM12878 cell lines, which loosely model the transition between normal and cancerous states in chronic myeloid leukemia (CML). In total, we identified 351 significantly altered TF co-regulation pairs. In particular, we found that the co-binding of the tumor suppressor BRCA1 and RNA polymerase II, a well-known transcriptional pair in healthy cells, was disrupted in tumors. Thus, DiNeR successfully extracted hub regulators and discovered well-known risk genes. CONCLUSIONS: Our method DiNeR makes it possible to quantify changes in co-regulatory networks and identify alterations to TF co-binding patterns, highlighting key disease regulators. Our method DiNeR makes it possible to quantify changes in co-regulatory networks and identify alterations to TF co-binding patterns, highlighting key disease regulators.

The expression of the acarbose biosynthesis gene cluster in Actinoplanes sp. SE50/110 is dependent on the growth phase.

BACKGROUND: Actinoplanes sp. SE50/110 is the natural producer of the diabetes mellitus drug acarbose, which is highly produced during the growth phase and ceases during the stationary phase. In previous works, the growth-dependency of acarbose formation was assumed to be caused by a decreasing transcription of the acarbose biosynthesis genes during transition and stationary growth phase. RESULTS: In this study, transcriptomic data using RNA-seq and state-of-the-art proteomic data from seven time points of controlled bioreactor cultivations were used to analyze expression dynamics during growth of Actinoplanes sp. SE50/110. A hierarchical cluster analysis revealed co-regulated genes, which display similar transcription dynamics over the cultivation time. Aside from an expected metabolic switch from primary to secondary metabolism during transition phase, we observed a continuously decreasing transcript abundance of all acarbose biosynthetic genes from the early growth phase until stationary phase, with the strongest decrease for the monocistronically transcribed genes acbA, acbB, acbD and acbE. Our data confirm a similar trend for acb gene transcription and acarbose formation rate. Surprisingly, the proteome dynamics does not follow the respective transcription for all acb genes. This suggests different protein stabilities or post-transcriptional regulation of the Acb proteins, which in turn could indicate bottlenecks in the acarbose biosynthesis. Furthermore, several genes are co-expressed with the acb gene cluster over the course of the cultivation, including eleven transcriptional regulators (e.g. ACSP50_0424), two sigma factors (ACSP50_0644, ACSP50_6006) and further genes, which have not previously been in focus of acarbose research in Actinoplanes sp. SE50/110. CONCLUSION: In conclusion, we have demonstrated, that a genome wide transcriptome and proteome analysis in a high temporal resolution is well suited to study the acarbose biosynthesis and the transcriptional and post-transcriptional regulation thereof.